HDACs are zinc metalloenzymes that catalyse the hydrolysis of acetylated lysine residues. In histones, this returns lysines to their protonated state and is a global mechanism of eukaryotic transcriptional control, resulting in tight packaging of DNA in the nucleosome. Additionally, reversible lysine acetylation is an important regulatory process for non-histone proteins. Thus, compounds which are able to modulate HDAC have important therapeutic potential.
The natural products FK228 (Structure I) and Spiruchostatin A (Structure II) are depsipeptides that have been reported to have potential as HDAC inhibitors. The term depsipeptide describes a class of oligopeptides or polypeptides that have both ester and peptide links the chain.
FK228 is a cyclic depsipeptide containing 4 monomer units together with a cross-ring bridge. This compound, under the trade name of Romidepsin®, has been tested as a therapeutic in human trials and shown that it has valuable effects on a number of diseases.
Spiruchostatin A is a cyclic depsipeptide that is structurally related to FK228: it is a cyclic depsipeptide containing a tri-peptide, a statine unit and a cross-ring bridge.

However, because both FK228 and Spiruchostatin A are natural products, they are not amenable to optimization for use as a therapeutic agent.
Analogues of these compounds are disclosed in WO2006/129105 (published after the priority dates claimed); further such compounds are disclosed in an unpublished PCT Application claiming priority from GB Patent Application No. 0623388.6. They may have improved HDAC inhibitory properties with respect to FK228 and Spiruchostatin A or other drug-like properties which make them more useful as medicines. These compounds have the general structures shown in Structures III, IV, V & VI wherein R1, R2, R3 and R4 are the same or different and represent an amino acid side chain moiety, each R6 is the same or different and represents hydrogen or C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, and Pr1 and Pr2 are the same or different and represent hydrogen or a thiol-protecting group.
Without being constrained by theory, it is believed that Structure IV where R1 is ═CH—CH3, R2 is —CH(CH3)2, R3 is —CH(CH3)2, R4 and R6 are both —H and Pr1 and Pr2 are both —H, is formed inside the cell from Structure I by reduction of the disulphide bond, and that the 4-thio-butyl-1-ene so formed is a critical part of the mechanism of action of the compound. Thus it has previously been suggested that compounds lacking this group will have reduced utility as therapeutic agents.

This concept is supported by the observation that FR-901375, a cyclic depsipeptide HDAC inhibitor with quite a different ring structure, has the same disulphide-containing bridge across the ring as is seen in FK228 and Spiruchostatin A.